Review Article

Gonadotropin‑releasing hormone analogs:

Understanding advantages and limitations
ABSTRACT
Pratap Kumar,
Alok Sharma1 Pituitary stimulation with pulsatile gonadotropin‑releasing hormone (GnRH) analogs
Department of Obstetrics and
induces both follicle‑stimulating hormone (FSH) and luteinizing hormone (LH). Pituitary
Gynecology, Kasturba Medical
College, Manipal University, gonadotropin secretions are blocked upon desensitization when a continuous GnRH
Manipal, Karnataka, stimulus is provided by means of an agonist or when the pituitary receptors are occupied
1
Department of Obstetrician with a competitive antagonist. GnRH antagonists were not available originally; therefore,
and Gynecologist, Deen Dayal prolonged daily injections of agonist with its desensitizing effect were used. Today,
Upadhyaya Hospital, Shimla,
Himachal Pradesh, India
single‑ and multiple‑dose injectable antagonists are also available to block the LH surge and
thus to cause desensitization. This review provides an overview of the use of GnRH analogs
Address for correspondence: which is potent therapeutic agents that are considerably useful in a variety of clinical
Dr. Pratap Kumar,
indications from the past to the future with some limitations. These indications include
Department of Obstetrics and
Gynecology, Kasturba Medical management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine
College, Manipal University, bleeding, premenstrual syndrome, assisted reproduction, and some hormone‑dependent
Manipal ‑ 576 104, tumours, other than ovulation induction.
Karnataka, India.
E‑mail: pratap.kumar@
manipal.edu

Received: 18.09.2014
Review completed: 23.09.2014
Accepted: 19.09.2014 KEY WORDS:  Advantages, gonadotropin‑releasing hormone analog, limitations

INTRODUCTION by GnRH‑receptor competition, thereby

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DOI:
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170
Gonadotropin‑releasing hormone (GnRH)
and its analogs have been extensively
used in clinical medicine since they
were identified and synthesized in 1971.
This was a logical consequence of the
discovery of the amino acid sequence of
GnRH, which led to the development of
agonistic and antagonistic analogs with
many scientific clinical perspectives.
Native GnRH stimulates gonadotrophs of
the anterior pituitary and has been used
for induction of ovulation. The GnRH
agonists are more potent and have got a
longer half‑life than native GnRH. They
produce an initial stimulation of pituitary
gonadotrophs that results in secretion of
follicle‑stimulating hormone (FSH) and
luteinizing hormone (LH) and the expected
gonadal response. This response is followed
by down‑regulation and inhibition of the
pituitary‑gonadal axis. As compared
to GnRH agonists, GnRH antagonists
promptly suppress pituitary gonadotropin
Journal of Human Reproductive Sciences / Volume 7 / Issue 3 / Jul - Sep 2014
avoiding the initial stimulatory phase
of the agonists. Discontinuation of
GnRH antagonist treatment leads to a
rapid and predictable recovery of the
pituitary‑gonadal axis. Agonists would
be used as strong sustained stimulators of
gonadotropin secretion and the antagonists
promised to be a potential tool for chemical
hypophysectomy. It was relatively simple
to develop safe agonist by just changing
one or two amino acids but it required
almost 30 years of trial and error with
replacement of three or more amino acids
to obtain an antagonist with an acceptable
pharmacokinetic, safety, and commercial
profile.
Half‑life of GnRH is 2-4 min as it is degraded
by peptidase and cleared by glomerular
filtration. This was the sole reason that of
GnRH, analogs with agonistic or antagonistic
properties have been synthesized to increase
their potency and duration. These properties
were developed by deleting, substituting
 Kumar and Sharma: GnRH analog, advantages, limitations
or modifying amino acid sequence at different positions
of GnRH.
Gonadotropin‑releasing hormone and its analogs are being
used therapeutically in many clinical conditions.
OVARIAN STIMULATION
As discussed earlier pulsatile administration of GnRH in
physiologic amounts at a frequency that is similar to the
endogenous release stimulates the ovaries which will induce
ovulation in anovulatory conditions, such as hypothalamic
amenorrhea and polycystic ovarian disease.[1]
Gonadotropin‑releasing hormone agonists in combination
with gonadotropins for ovarian stimulation in assisted
reproductive technology  (ART) have been extensively
investigated. The above combination also termed as
“Superovulation therapy” is very effective in women
who respond poorly to gonadotropin stimulation or
who have premature ovulation. Benefits of this therapy
seem to be suppression of endogenous gonadotropin
release, prevention of premature ovulation, recovery of
a larger number of oocytes, a decrease in the number of
canceled cycles, and an increase in pregnancy rate. Now,
GnRH antagonists also have been used during the late
follicular phase of normal menstrual cycles as well as
gonadotropin‑stimulated cycles.[2]
TREATMENT REGIMENS
There are many treatment schedules in which GnRH
agonists in ART. Their duration and initiation particularly
in ovarian hyperstimulation in vitro fertilization (IVF)/
intracytoplasmic sperm injection treatments varies. One
can start the treatment either in the early follicular or
midluteal phase of the preceding cycle. This cycle may be
spontaneous or may be under the influence of progestagens
and/or estrogens.
Long or desensitization protocol
The idea is to suppress LH hormone so that there is
no sudden rise of the same. In this type of protocol the
agonist starts in the early, mid-, or late luteal phase in
the preceding cycle or the follicular phase until human
chorionic gonadotropin (hCG) administration. However,
starting in the early luteal phase showed lesser number
of eggs retrieved compared to the follicular phase start.[3]
More of the dosages of Gonadotropin were needed in
the long protocol compared to the other regeems like
ultrashort, short and higher number of eggs were obtained
as shown in a meta analysis[4] when compared to the long
follicular phase protocol more profound and prompt
suppression was found after midluteal administration.[5]
Journal of Human Reproductive Sciences / Volume 7 / Issue 3 / Jul - Sep 2014
Among many advantages one of the major advantages of
the long protocol of GnRH agonist administration is that
the initiation of exogenous gonadotropins after pituitary
desensitization can be delayed to prevent ovum pickup
(OPU) in the weekends (the so-called “programming”),
without any detrimental effect on IVF outcome. [6]
Furthermore, delay in hCG administration for 24-48 h
seemed to improve fecundity and contributes to planning
of the OPU.[7,8] Ideally the GnRH agonist should be started
one week before the expected menses. There is an initial
flare up of the FSH and LH but this seems to lasting for
a short time. Later the receptors are downloaded in the
pituitary to a very low level. Except PCOS , all other
women the dose can be halved when the menses starts
and Gonadotropins can be stated for stimulation of the
follicles. This kind of half the dose continuation along
with gonadotropins keeps the LH at a low levels rather
than getting the surges.[9] The agonist is given on the day
of hCG also.The agonist depletes the receptor, which
regenerates only long after the agonist administration
is stopped. However, sometimes the dose used may be
excessive, causing too much of suppression of the ovaries.
All this kind of suppression will cause luteal phase defect,
which, therefore, needs supplementation. [10] Ovarian
hyper stimulation syndrome has to be thought of when
high dose is used for ovarian stimulation. Some of the
women have a cyst on the second day of menses and this
is one of the side effect of starting the GnRH analogue in
the luteal phase, which leads to cancellation of the cycle.
Short protocol
Instead of starting the GnRH analogue in the luteal phase
of the cycle it can be started at the beginning of the cycle.
This leads to the flare effect of FSH and LH and augments
the folliculogenesis already in progress. Though follicles
are recruited with this method, the excess of LH in the
early part may be deleterious to the growing follicle. With
this method the dosage of gonadotropins can be reduced
for an initial period of 2-3 days at least, wherein the cost
would come down. The dose of agonist it is stopped when
the follicular maturity is attained and ovulation triggering
planned with hCG. This is one of the methods chosen for
a poor responder.
Microdose flare protocol
This is not very popular and is very similar to the short
protocol except that the dose of agonist is reduced.[11]
Stoping gonadotropin‑releasing hormone agonist protocol
In this protocol though the GnRH analogue is started in the
luteal phase one week before the expected start of menses,
is it stopped at the initiation of gonadotropin therapy since
the suppression is less to start the gonadotropins. However
this is not popular due to the irratic response.[10,12]
171
 Kumar and Sharma: GnRH analog, advantages, limitations
Ultrashort protocol
Gonadotropins are started on the day of the menses
and the agonist is also started but stopped in 2-3 days,
as the suppression will outlast the stimulation.[13] In
general, protocols of short, microdose fl are, preparatory
protocol/stop GnRH-a, ultrashort are not popular due to
the erratic responses.
ANTAGONIST PROTOCOLS
Unlike GnRH agonists, there is no hypersecretion of
gonadotropins but instead cause an immediate and
rapid, reversible suppression of gonadotropin secretion.
The principal mechanism of action of GnRH antagonists
is competitive occupancy of the GnRH-receptor. Here
the antagonists are are started half way through the
gonadotropin stimulation so that the LH suppression is
done and LH surge is prevented.
Single‑dose protocol
The Ovarian stimulation is done with gonadtropins starting
on day 2 or 3 of the menstrual cycle. The antagonist is given
on day 7 as a fi xed protocol (French protocol).[14] Once a
single injection is given the LH surge prevention is seen for
the next 4 days. In case the patient does not get ready for hCG
trigger within this time frame, she is given additional daily
doses and including the day of hCG trigger. This protocol
is easy to use, well-tolerated with only mild and transient
injection site reactions, and ensures patient compliance.
Multiple‑dose protocol
The stimulation wth gonadotropins is started on day 2 or
3 of the menstrual cycle. In the fl exible protocol (Ludwing
protocol), GnRH antagonist is started once the leading
follicle is ≥14 mm.[15] When the multiple-dose protocol is
done, it avoids profound LH suppression which causes
severe decrease in estradiol levels often seen in single-dose
protocol.
Multiple-dose protocol is a simple, safe, and effi cient
approach for preventing LH surge. On the other hand, the
fl exible protocol avoids unnecessary injections when risk
of LH surge is minimal and hence uses less total antagonist
ampoules and less gonadotropins. Hence, it appears as a
more cost-eff ective approach.[15]
There is a role of agonist as a trigger for ovulation induction
instead of hCG to avoid Ovarian hyper stimulation
syndrome and can be used in an antagonist cycle or in a
intrauterine insemination cycle when the follicle is large.
Precocious puberty
It is a well‑known fact that maturation of the pituitary-
gonadal system requires pulsatile GnRH stimulation.
172 Journal of Human Reproductive Sciences / Volume 7 / Issue 3 / Jul - Sep 2014
Idiopathic precocious puberty is the disorder characterized
by premature GnRH activity. The aim of various
therapeutic methods was to suppress the pituitary
gonadal function, in precocious puberty also long‑term
administration of GnRH agonists has proved remarkably
safe and effective.[16,17]
Within 6-18  months of daily treatment with an agonist,
pubertal levels and patterns of secretion of gonadotropins
and sex hormones revert back to prepubertal levels and
patterns. One more beneficial effect of this therapy is the
regression of secondary sexual characters and stoppage
of menstrual bleeding and as soon as the treatment is
discontinued, gonadotropin and steroid genesis resume.
After which the child follows the expected clinical
progression through normal puberty.
A variety of GnRH agonists have been used to treat precocious
puberty In Europe, deslorelin, decapeptyl, triptorelin, and
buserelin have been most commonly used. In the United
States, nafarelin  (800-1800  mcg/day intramuscularly) or
leuprolide (4-50 mcg/kg/day subcutaneously) have been
found to be effective.[18]
Delayed puberty
Long‑term pulsatile administration of GnRH may initiate
puberty in both boys and girls with delayed puberty.[17]
Endometriosis
Endometriosis is characterized by presence of ectopic
endometrial implants which are subjected to the same
cyclical hormonal influences as normal endometrium. Its
management by GnRH agonists is based on their ability
to produce amenorrhea and anovulation. Initially the
therapeutic response characterized by an initial increase
in gonadotropins and estradiol followed by sustained
hypoestrogenism, amenorrhea, and anovulation. Several
controlled and randomized trials have shown that if GnRH
agonists are used for the treatment of endometriosis for
at least 6 months have shown to induce amenorrhea,
anovulation, and regression of endometriosis and its
associated clinical symptoms.
Uterine leiomyomata (fibroids)
These are the most common benign tumors of female
reproductive tract. Nothing has to be done for asymptomatic
ones unless their large size, rapid growth, or degeneration
causes symptoms requiring intervention. Prompt action is
required when fibroids are associated with menorrhagia
or other menstrual disorders. Leiomyomata may also be
associated with infertility, and the incidence of spontaneous
pregnancy loss seems to be higher in patients who have
these tumors. It has been recognized that estrogen is the
 Kumar and Sharma: GnRH analog, advantages, limitations
trigger factor for the growth of leiomyomata. These tumors
regress in hypoestrogenic states, like menopause. The basis
for the medical treatment of leiomyomata with GnRH
agonists is that they produce profound hypoestrogenic
state. The use of GnRH agonists in the treatment of
leiomyomata may eliminate the need for surgery in
selected cases (i.e. perimenopausal or high‑risk surgical) or
decrease the surgical risk (e.g. diminished size of remaining
fibroid tissue) when surgery is contemplated. Thus, the
main goal of the pretreatment with GnRH agonists is to
reduce the blood loss during surgery, and the reduced size
of the tumor makes operation less complicated. However,
the reduction in size following GnRH‑a is about 50% and
may grow once treatment is stopped. Add‑back therapy is
not useful in conjunction with GnRH agonists for treatment
of women with leiomyomata. Although these women also
have the side effects associated with hypoestrogenism,
adding hormone replacement therapy (HRT) (estrogen and
progesterone) counteracts the desired hypoestrogen effect
needed to shrink the tumor.[17]
Hormone‑dependent tumors
Some hormone‑dependent and malignant tumors of the
breast, ovary, and endometrium, are treated with the
high doses of GnRH agonists. This causes suppression
of gonadotropin secretion.[19,20] This mechanism causes
decreased secretion of pituitary gonadotropin and gonadal
steroids, resulting in medical castration. These agents have
direct effect steroidogenesis of target tissues.
Hirsutism
Hirsutism is caused by excessive androgens by the ovaries
or adrenals and increased sensitivity of the hair follicles to
normal circulating androgen levels. These hyperandrogenic
states in women are frequently associated to polycystic
ovarian disease. Suppression of ovarian function with
GnRH agonists has been found to be beneficial in hirsute
women. With the reduction in hirsutism this therapy also
decreases serum levels of gonadotropin, total testosterone,
free testosterone, and androstenedione. Some of the clinical
trials have evaluated the effectiveness of adding sex
hormones to GnRH agonist therapy as add‑back therapy
have further decreases serum testosterone levels, reduces
the hypoestrogenic side effects of analogs, and results in
greater reduction of hirsutism.[21]
Dysfunctional uterine bleeding
Dysfunctional uterine bleeding (DUB) is the most common
disorder characterized with anovulation or oligo‑ovulation
in the absence of organic or systemic disease. One of the
effective medical managements of DUB associated with
abnormal and acyclic bleeding is suppression of the ovarian
function with GnRH agonists. Due to the increased expenses,
GnRH‑a is not popular for DUB. In long‑term treatment for
Journal of Human Reproductive Sciences / Volume 7 / Issue 3 / Jul - Sep 2014
DUB, add back therapy with HRT should be supplemented
to avoid the side effects related to hypoestrogenism.
Endometrial ablation
The aim of this procedure was to sufficiently eliminate
or suppress menstrual flow to avoid the level of anemia
requiring a hysterectomy. Endometrial ablation entails
destruction of the entire endometrial layer by means of laser,
electrocautery, electrosection, or heating, leaving the uterine
cavity intact but scarred and devoid of endometrium. To
achieve maximum ablation, the endometrium should be as
thin as possible at the start of ablative treatment. Because of
their hypoestrogenic effects, GnRH agonists in usual doses
administered for approximately 8 weeks have been found
to be very effective in achieving the desired endometrial
thinning before the procedure.[22] Once again, this prolonged
use is expensive.
Premenstrual syndrome
It is characterized by irritability, depression, and fatigue
accompanied by bloating, breast tenderness, and/or
headache during the luteal phase of the cycle. Though it
has been reported in 80% of the women in reproductive age
group but if strict diagnostic criteria have been used only
5% have suggested.[23] some of the behavioral symptoms
seen in premenstrual syndrome (PMS) are labile mood,
hypersensitive nature, crying spells, social withdrawal, and
difficulty in concentration.
Treatment of PMS with GnRH analogs as long‑term
treatment has been limited due to hyoestrogenic side
effects, loss of bone mineral density and cost. But with the
advent of add‑back therapy, there has been a resurgence of
interest in treating this condition with GnRH analogs. As
expected, GnRH agonist treatment markedly alleviated PMS
symptoms. The addition of estrogen, medroxyprogesterone
acetate, or a combination of these agents was equally
effective, whereas placebo treatment alone was associated
with some increase in symptoms compared with GnRH
agonist therapy alone. However, GnRH‑a for PMS is not
popular due to the high cost.
Role of GnRH analogue for fertility preservation during
chemotherapy
Due to the severe suppression of the follicles in the ovary,
GnRH – a can be used to protect the oocytes prior to starting
of the chemotherapy. Cochrane review confirms the role of
GnRH- a before chemotherapy and suggest that this is given
throughout the chemotherapy duration.[24]
SUMMARY
This review is an overview of the use of GnRH analogs
which is potent therapeutic agents that are considerably
173
 Kumar and Sharma: GnRH analog, advantages, limitations

useful in a variety of clinical indications from the past to
the future with some limitations.
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How to cite this article: Kumar P, Sharma A. Gonadotropin-releasing
hormone analogs: Understanding advantages and limitations.
J Hum Reprod Sci 2014;7:170-4.
Source of Support: Nil, Conflict of Interest: None declared.

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